title: TLR2 polymorphisms influence neonatal regulatory T cells depending on maternal atopy.
abstract: BACKGROUND
  Toll-like receptor (TLR) polymorphisms have been associated with atopic diseases in children and adults. Development of atopic diseases may be modified by TLR-mediated signals that modulate T-regulatory cells (Tregs) early in life when maternal influences are still present and relevant. The aim of this study was to assess whether genetic TLR variants influence Tregs in neonates.
  
  
  METHODS
  Twelve single nucleotide polymorphisms located in TLR1, TLR2, TLR4, TLR6, and TLR10 were genotyped in 200 cord blood samples (72 samples from atopic, 128 from nonatopic mothers). Cord blood mononuclear cells were cultured without or with stimulation [lipid A (LpA), peptidoglycan (Ppg), phytohemagglutinin, house dust mite]. mRNA expression of Treg marker genes [forkhead box protein P3 (FOXP3), glucocorticoid-induced tumor necrosis factor receptor (GITR), lymphocyte activation gene 3 (LAG3)], TLR2, Th1/Th2 cytokines, and tumor necrosis factor alpha (TNF-α) was measured.
  
  
  RESULTS
  In children with the AA genotype of the TLR2 promoter variant rs4696480, gene expression of FOXP3 and Treg marker genes GITR and LAG3 as well as Th2 cytokines and TNF-α secretion was significantly increased in the presence of maternal atopy and Tregs decreased without maternal atopy. In carriers of the GG genotype for TLR2 rs1898830, gene expression of Treg marker genes was significantly decreased with and increased without maternal atopy. FOXP3 expression was also modified by TLR1 rs4833095 (P ≤ 0.03) and trendwise by TLR10 rs4129009 after LpA and Ppg stimulation.
  
  
  CONCLUSIONS
  Genetic variations of TLR2, TLR1, and TLR10 affect Treg marker gene expression in cord blood. Gene-immunological interactions of the TLR pathway influence Tregs early in life, modulated by maternal atopy. This may be relevant for immune maturation in the development of atopic diseases in childhood.
authors.affiliation: Department of Pulmonary & Allergy, University Children's Hospital Munich, LMU Munich, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Liu
authors.forename: D
authors.initials: D
authors.lastname: Rädler
authors.forename: S
authors.initials: S
authors.lastname: Illi
authors.forename: E
authors.initials: E
authors.lastname: Klucker
authors.forename: E
authors.initials: E
authors.lastname: Turan
authors.forename: E
authors.initials: E
authors.lastname: von Mutius
authors.forename: M
authors.initials: M
authors.lastname: Kabesch
authors.forename: B
authors.initials: B
authors.lastname: Schaub
mesh_terms: D015415:Biomarkers / Q000032:analysis; D005260:Female; D005312:Fetal Blood / Q000166:cytology; D005838:Genotype; D006801:Humans; D006969:Hypersensitivity, Immediate; D007231:Infant, Newborn; D008431:Maternal-Fetal Exchange; D009035:Mothers; D011110:Polymorphism, Genetic / Q000276:immunology*; D020641:Polymorphism, Single Nucleotide; D011247:Pregnancy; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D051194:Toll-Like Receptor 1; D051201:Toll-Like Receptor 10; D051195:Toll-Like Receptor 2 / Q000235:genetics*
chemical_list: D015415:Biomarkers; C475955:TLR10 protein, human; C495342:TLR2 protein, human; D051194:Toll-Like Receptor 1; D051201:Toll-Like Receptor 10; D051195:Toll-Like Receptor 2